1. Field of the Invention
The present invention relates to 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives. More particularly, the invention relates to 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives derived from .alpha.,.alpha.-disubstituted .alpha.-amino acids and optically active forms thereof.
The 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives of the invention are those in which a hydroxyl group is introduced to the .beta.-position of the carboxylic acid and the .alpha.- and the .beta.-positions are linked to form a cyclic system whereby the conformation of the hydroxyl group at the .beta.-position is controlled. When the 1-amino-2-hydroxycycloalkanecarboxylic acid derivative of the present invention is introduced into a peptide or protein molecule in place of a normal amino acid, the conformation of the obtained peptide or protein molecule can be fixed. Therefore, the compounds of the invention can play an important role in peptide and protein engineering.
The 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives of the present invention can be regarded as cyclic amino acid derivatives equivalent to naturally occurring hydroxyamino acids such as serine and threonine.
2. Description of the Prior Art
Peptides having .alpha.-substituted amino acid(s) in the molecule have been arousing interest in their physiological activities because of their resistance against peptidases resulting from the steric hindrance at the peptide linkage sites and because of their enzyme-inhibiting activities resulting from the stabilized conformation in .alpha.-helical structure. For example, in peptides, when amino acids such as serine, phenylalanine and aspartic acid are replaced by .alpha.-substituted amino acids, hydrolysis of the peptide bonds with peptidases can be inhibited and the conformation of the peptides can be stabilized, and therefore such peptides have been drawing attention from a viewpoint of development of enzyme inhibitors and the like.
On the other hand, serine and threonine which constitute physiologically active peptide often act as the active centers of receptors and enzymes. Therefore, it has also been arousing interest to introduce an amino acid derivative having a conformationally controlled hydroxyl group into a peptide or protein molecule in place of naturally occurring amino acids such as serine and threonine and to study the effectiveness of such introduction on physiological activity and the correlation between the structure and the activity of the peptide or protein molecule.
Heretofore, several types of .alpha.-substituted amino acids have been reported, including .alpha.-substituted serine derivatives such as 2-methylserine (2-hydroxymethylalanine) and 2-phenylserine (2-hydroxymethyl-2-phenylglycine) (D. Seebach et al., Tetrahedron Letters., vol. 24, p.3311, 1983; Ito et al., ibid., vol.29, p.235, 1988), 2-hydroxymethylphenylalanine and 2-hydroxymethylaspartic acid (Japanese Patent Application Laid-open No. 8-337558).
However, any type of 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives in which the conformation of the hydroxyl group at the .beta.-position is controlled by cyclically linking the .alpha.-position and the .beta.-position have not been reported yet, other than 5-membered cyclic racemic amino acids (D. E. Gaitanopoulous et al.,: J. Med. Chem., vol. 19, p.342, 1976).